The overarching goal of the Washington University O'Brien Urology Center is to bring together an interdisciplinary team of outstanding investigators to apply and share their individual unique expertise and talents to address the mechanistic bases for common problems in benign urological diseases. These include bladder pain syndrome, overactive bladder, voiding dysfunction, and similar bladder symptoms, including referred pain, that result from urinary tract infections and other injuries or conditions that affet the urothelium. The themes that justify bringing these research groups under the umbrella of a synergistic U54 Cooperative Center are their shared interests in defining relationships between the urothelium and the nervous system, with focus on multiple effects of cellular injury to the urothelium and how this results in the perception of pain. There are three projects that will address different but overlapping aspects of bladder injury and pain responses. Project 1 (Mysorekar) will examine the involvement of inflammatory signals, estrogen, and aging in urothelial injury and bladder sensation in mice; Project 2 (Jain) will focus on the molecular mechanisms and genetics of GFL-Ret signaling in bladder innervation and injury in mouse models and in patients; and Project 3 (Gereau and Andriole) will use optogenetics in mice to map sensory neurons relevant to bladder injury and therapy and perform a clinical study of the effectiveness of a neurotransmitter receptor blocker to attenuate pain in relevant patients. These research projects will be supported by a Preclinical Models Core (Mysorekar and Gereau) and a Human Studies Core (Jain and Lai). The Administrative Core (Andriole and Miner) will oversee the operations of the Center and the Educational Enrichment Program, which is designed to provide undergraduates with the opportunity to perform research in urology and to host speakers for informing the urology communities at WashU of the latest research findings. Opportunity Pool funds will support Pilot & Feasibility studies and will foster the use of banked human specimens and clinical information by urology researchers at other NIDDK-supported sites.